Iron-regulatory proteins (IRPs) 1 and 2 posttranscriptionally regulate expression of
transferrin receptor (TfR),
ferritin, and other
iron metabolism
proteins. Mice with targeted deletion of IRP2 overexpress
ferritin and express abnormally low TfR levels in multiple tissues. Despite this misregulation, there are no apparent pathologic consequences in tissues such as the liver and kidney. However, in the central nervous system, evidence of abnormal
iron metabolism in IRP2-/- mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss. Here, we report that ablation of IRP2 results in
iron-limited erythropoiesis. TfR expression in erythroid precursors of IRP2-/- mice is reduced, and bone marrow
iron stores are absent, even though
transferrin saturation levels are normal. Marked overexpression of 5-aminolevulinic
acid synthase 2 (Alas2) results from loss of IRP-dependent translational repression, and markedly increased levels of free
protoporphyrin IX and
zinc protoporphyrin are generated in IRP2-/- erythroid cells. IRP2-/- mice represent a new paradigm of genetic microcytic
anemia. We postulate that IRP2 mutations or deletions may be a cause of refractory microcytic
anemia and bone marrow
iron depletion in patients with normal
transferrin saturations, elevated serum
ferritins, elevated red cell
protoporphyrin IX levels, and adult-onset neurodegeneration.